Abstract
Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.
Keywords:
Alzheimer’s disease; translocator protein ligand; function modulators.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / metabolism
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Animals
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Cell Survival / drug effects
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Cells, Cultured
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Disease Models, Animal
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Drug Evaluation, Preclinical
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Humans
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Ligands
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Mice
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Molecular Structure
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Neuroprotective Agents / chemical synthesis
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / pharmacology*
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Protein Aggregation, Pathological / drug therapy*
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Protein Aggregation, Pathological / metabolism
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Protein Aggregation, Pathological / pathology
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Small Molecule Libraries / chemical synthesis
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Transcriptional Regulator ERG / antagonists & inhibitors
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Transcriptional Regulator ERG / metabolism
Substances
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Amyloid beta-Peptides
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ERG protein, human
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Ligands
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Neuroprotective Agents
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Small Molecule Libraries
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Transcriptional Regulator ERG
Grants and funding
This work was supported by the National Research Council of Science and Technology grant by the Korea government (MSIP) [No. CRC-15–04-KIST].